System and process for retina phototherapy

ABSTRACT

A system for treating retinal diseases includes passing a laser light beam through an optical lens or mask to optically shape the light beam. The light beam is applied to at least a portion of the retina. Due to the selected parameters of the laser light beam pulse length, power and duty cycle, the laser light beam can be applied to substantially the entire retina, including the fovea, without damaging retinal or foveal tissue, while still attaining the benefits of retinal photocoagulation.

RELATED APPLICATION

This is a Continuation of U.S. application Ser. No. 13/481,124 filed May25, 2012, which issued on Jul. 5, 2016 as U.S. patent application Ser.No. 9,381,115.

BACKGROUND OF THE INVENTION

The present invention generally relates to phototherapy orphotostimulation of biological tissue, such as laser retinalphotocoagulation therapy. More particularly, the present invention isdirected to a system and process for treating retinal diseases anddisorders by using harmless, subthreshold phototherapy orphotostimulation of the retina.

Complications of diabetic retinopathy remain a leading cause of visionloss in people under sixty years of age. Diabetic macular edema is themost common cause of legal blindness in this patient group. Diabetesmellitus, the cause of diabetic retinopathy, and thus diabetic macularedema, is increasing in incidence and prevalence worldwide, becomingepidemic not only in the developed world, but in the developing world aswell. Diabetic retinopathy may begin to appear in persons with Type I(insulin-dependent) diabetes within three to five years of diseaseonset. The prevalence of diabetic retinopathy increases with duration ofdisease. By ten years, 14%-25% of patients will have diabetic macularedema. By twenty years, nearly 100% will have some degree of diabeticretinopathy. Untreated, patients with clinically significant diabeticmacular edema have a 32% three-year risk of potentially disablingmoderate visual loss.

Until the advent of thermal retinal photocoagulation, there wasgenerally no effective treatment for diabetic retinopathy. Usingphotocoagulation to produce photothermal retinal burns as a therapeuticmaneuver was prompted by the observation that the complications ofdiabetic retinopathy were often less severe in eyes with preexistingretinal scarring from other causes. The Early Treatment of DiabeticRetinopathy Study demonstrated the efficacy of argon laser macularphotocoagulation in the treatment of diabetic macular edema.Full-thickness retinal laser burns in the areas of retinal pathologywere created, visible at the time of treatment as white or gray retinallesions (“suprathreshold” retinal photocoagulation). With time, theselesions developed into focal areas of chorioretinal scarring andprogressive atrophy.

With visible endpoint photocoagulation, laser light absorption heatspigmented tissues at the laser site. Heat conduction spreads thistemperature increase from the retinal pigment epithelium and choroid tooverlying non-pigmented and adjacent unexposed tissues. Laser lesionsbecome visible immediately when damaged neural retina overlying thelaser sight loses its transparency and scatters white ophthalmoscopiclight back towards the observer.

There are different exposure thresholds for retinal lesions that arehaemorrhagic, ophthalmoscopically apparent, or angiographicallydemonstrable. A “threshold” lesion is one that is barely visibleophthalmoscopically at treatment time, a “subthreshold” lesion is onethat is not visible at treatment time, and “suprathreshold” lasertherapy is retinal photocoagulation performed to a readily visibleendpoint. Traditional retinal photocoagulation treatment requires avisible endpoint either to produce a “threshold” lesion or a“suprathreshold” lesion so as to be readily visible and tracked. Infact, it has been believed that actual tissue damage and scarring arenecessary in order to create the benefits of the procedure. The gray towhite retinal burns testify to the thermal retinal destruction inherentin conventional threshold and suprathreshold photocoagulation.Photocoagulation has been found to be an effective means of producingretinal scars, and has become the technical standard for macularphotocoagulation for diabetic macular edema for nearly 50 years.

With reference now to FIG. 1, a diagrammatic view of an eye, generallyreferred to by the reference number 10, is shown. When usingphototherapy, the laser light is passed through the patient's cornea 12,pupil 14, and lens 16 and directed onto the retina 18. The retina 18 isa thin tissue layer which captures light and transforms it into theelectrical signals for the brain. It has many blood vessels, such asthose referred to by reference number 20, to nourish it. Various retinaldiseases and disorders, and particularly vascular retinal diseases suchas diabetic retinopathy, are treated using conventional thermal retinalphotocoagulation, as discussed above. The fovea/macula region, referredto by the reference number 22 in FIG. 1, is a portion of the eye usedfor color vision and fine detail vision. The fovea is at the center ofthe macula, where the concentration of the cells needed for centralvision is the highest. Although it is this area where diseases such asage-related macular degeneration are so damaging, this is the area whereconventional photocoagulation phototherapy cannot be used as damagingthe cells in the foveal area can significantly damage the patient'svision. Thus, with current convention photocoagulation therapies, thefoveal region is avoided.

That iatrogenic retinal damage is necessary for effective lasertreatment of retinal vascular disease has been universally accepted foralmost five decades, and remains the prevailing notion. Althoughproviding a clear advantage compared to no treatment, current retinalphotocoagulation treatments, which produce visible gray to white retinalburns and scarring, have disadvantages and drawbacks. Conventionalphotocoagulation is often painful. Local anesthesia, with its ownattendant risks, may be required. Alternatively, treatment may bedivided into stages over an extended period of time to minimizetreatment pain and post-operative inflammation. Transient reduction invisual acuity is common following conventional photocoagulation.

In fact, thermal tissue damage may be the sole source of the manypotential complications of conventional photocoagulation which may leadto immediate and late visual loss. Such complications includeinadvertent foveal burns, pre- and sub-retinal fibrosis, choroidalneovascularization, and progressive expansion of laser scars.Inflammation resulting from the tissue destruction may cause orexacerbate macular edema, induced precipitous contraction offibrovascular proliferation with retinal detachment and vitreoushemorrhage, and cause uveitis, serous choroidal detachment, angleclosure or hypotony. Some of these complications are rare, while others,including treatment pain, progressive scar expansion, visual field loss,transient visual loss and decreased night vision are so common as to beaccepted as inevitable side-effects of conventional laser retinalphotocoagulation. In fact, due to the retinal damage inherent inconventional photocoagulation treatment, it has been limited in densityand in proximity to the fovea, where the most visually disablingdiabetic macular edema occurs.

Notwithstanding the risks and drawbacks, retinal photocoagulationtreatment, typically using a visible laser light, is the currentstandard of care for proliferative diabetic retinopathy, as well asother retinopathy and retinal diseases, including diabetic macular edemaand retinal venous occlusive diseases which also respond well to retinalphotocoagulation treatment. In fact, retinal photocoagulation is thecurrent standard of care for many retinal diseases, including diabeticretinopathy.

Another problem is that the treatment requires the application of alarge number of laser doses to the retina, which can be tedious andtime-consuming. Typically, such treatments call for the application ofeach dose in the form of a laser beam spot applied to the target tissuefor a predetermined amount of time, from a few hundred milliseconds toseveral seconds. Typically, the laser spots range from 50-500 microns indiameter. Their laser wavelength may be green, yellow, red or eveninfrared. It is not uncommon for hundreds or even in excess of onethousand laser spots to be necessary in order to fully treat the retina.The physician is responsible for insuring that each laser beam spot isproperly positioned away from sensitive areas of the eye, such as thefovea, that could result in permanent damage. Laying down a uniformpattern is difficult and the pattern is typically more random thangeometric in distribution. Point-by-point treatment of a large number oflocations tends to be a lengthy procedure, which frequently results inphysician fatigue and patient discomfort.

U.S. Pat. No. 6,066,128, to Bahmanyar describes a method of multi-spotlaser application, in the form of retinal-destructive laserphotocoagulation, achieved by means of distribution of laser irradiationthrough an array of multiple separate fiber optic channels and microlenses. While overcoming the disadvantages of a point-by-point laserspot procedure, this method also has drawbacks. However, a limitation ofthe Bahmanyar method is differential degradation or breakage of thefiber optics or losses due to splitting the laser source into multiplefibers, which can lead to uneven, inefficient and/or suboptimal energyapplication. Another limitation is the constraint on the size anddensity of the individual laser spots inherent in the use of an opticalsystem of light transmission fibers in micro lens systems. Themechanical constraint of dealing with fiber bundles can also lead tolimitations and difficulties focusing and aiming the multi-spot array.

U.S. Patent Publication 2010/0152716 A1 to Previn describes a differentsystem to apply destructive laser irradiation to the retina using alarge retinal laser spot with a speckle pattern, oscillated at a highfrequency to homogenize the laser irradiance throughout the spot.However, a problem with this method is the uneven heat buildup, withhigher tissue temperatures likely to occur toward the center of thelarge spot. This is aggravated by uneven heat dissipation by the ocularcirculation resulting in more efficient cooling towards the margins ofthe large spot compared to the center. That is, the speckle patternbeing oscillated at a high frequency can cause the laser spots to beoverlapping or so close to one another that heat builds up andundesirable tissue damage occurs. Previn's speckle technique achievesaveraging of point laser exposure within the larger exposure via therandom fluctuations of the speckle pattern. However, such averagingresults from some point exposures being more intense than others,whereas some areas within the exposure area may end with insufficientlaser exposure, whereas other areas will receive excessive laserexposure. In fact, Previn specifically notes the risk of excessiveexposure or exposure of sensitive areas, such as the fovea, which shouldbe avoided with this system. Although these excessively exposed spotsmay result in retinal damage, Previn's invention is explicitly intendedto apply damaging retinal photocoagulation to the retina, other than thesensitive area such as the fovea.

However, all conventional retinal photocoagulation treatments, includingthose described by Previn and Bahmanyar, create visible endpoint laserphotocoagulation in the form of gray to white retinal burns and lesions,as discussed above. Recently, the inventor has discovered thatsubthreshold photocoagulation in which no visible tissue damage or laserlesions were detectable by any known means including ophthalmoscopy;infrared, color, red-free or autofluorescence fundus photography instandard or retro-mode; intravenous fundus fluorescein or indocyaninegreen angiographically, or Spectral-domain optical coherence tomographyat the time of treatment or any time thereafter has produced similarbeneficial results and treatment without many of the drawbacks andcomplications resulting from conventional visible threshold andsuprathreshold photocoagulation treatments. It has been determined thatwith the proper operating parameters, subthreshold photocoagulationtreatment can be, and may ideally be, applied to the entire retina,including sensitive areas such as the fovea, without visible tissuedamage or the resulting drawbacks or complications of conventionalvisible retinal photocoagulation treatments. Moreover, by desiring totreat the entire retina, or confluently treat portions of the retina,laborious and time-consuming point-by-point laser spot therapy can beavoided. In addition, the inefficiencies and inaccuracies inherent toinvisible endpoint laser treatment resulting in suboptimal tissue targetcoverage can also be avoided.

SUMMARY OF THE INVENTION

The present invention resides in a process and system for treatingretinal diseases and disorders by means of harmless, subthresholdphotocoagulation phototherapy. Although the present invention isparticularly useful in treating diabetic retinopathy, including diabeticmacular edema, it will be understood that the present invention alsoapplies to all other retinal conditions, including but not limited toretinal venous occlusive diseases and idiopathic central serouschorioretinopathy, proliferative diabetic retinopathy, and retinalmacroaneurysm as reported, which respond well to traditional retinalphotocoagulation treatments; but having potential application aspreventative and rejuvenative in disorders such as genetic diseases andage-related macular degeneration and others.

In accordance with the present invention, a system for treating retinaldiseases and disorders comprises a laser producing a micropulsed lightbeam. In a particularly preferred embodiment, the laser produces a lightbeam having an infrared wavelength, such as between 750 nm-1300 nm, andpreferably approximately 810 nm. The light beam has an intensity ofbetween 100-590 watts per square centimeter, and preferablyapproximately 350 watts per square centimeter. The pulse length of thelaser is 500 milliseconds or less. The laser has a duty cycle of lessthan 10%, and typically approximately 5%.

An optical lens or mask optically shapes the light beam from the laserinto a geometric object or pattern. For example, the optical lens ormask, such as a diffraction grating, produces a simultaneous pattern ofspaced apart laser spots.

An optical scanning mechanism controllably directs the light beam objector pattern onto the retina. The light beam geometric object or patternis incrementally moved a sufficient distance from where the light beamwas previously applied to the retina, to avoid tissue damage, prior toreapplying the light beam to the retina.

The light beam is applied to at least a portion of the retina, such asat eighteen to fifty-five times the American National StandardsInstitute (ANSI) maximum permissible exposure (MPE) level. Given theparameters of the generated laser light beam, including the pulselength, power, and duty cycle, no visible laser lesions or tissue damageis detectable ophthalmoscopically or angiographically after treatment,allowing the entire retina, including the fovea, to be treated withoutdamaging retinal or foveal tissue while still providing the benefits ofphotocoagulation treatment.

Other features and advantages of the present invention will becomeapparent from the following more detailed description, taken inconjunction with the accompanying drawings, which illustrate, by way ofexample, the principles of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings illustrate the invention. In such drawings:

FIG. 1 is a cross-sectional diagrammatic view of a human eye;

FIGS. 2A-2F are graphic representations of the effective surface area ofvarious modes of retinal laser treatment;

FIG. 3 is a diagrammatic view illustrating a system used for treating aretinal disease or disorder in accordance with the present invention;

FIG. 4 is a diagrammatic view of an exemplary optical lens or mask usedto generate a geometric pattern, in accordance with the presentinvention;

FIG. 5 is a top plan view of an optical scanning mechanism, used inaccordance with the present invention;

FIG. 6 is a partially exploded view of the optical scanning mechanism ofFIG. 5, illustrating the various component parts thereof;

FIG. 7 illustrates controlled offset of exposure of an exemplarygeometric pattern grid of laser spots to treat the retina in accordancewith the present invention;

FIG. 8 is a diagrammatic view illustrating the units of a geometricobject in the form of a line controllably scanned to treat an area ofthe retina in accordance with the present invention;

FIG. 9 is a diagrammatic view similar to FIG. 8, but illustrating thegeometric line or bar rotated to treat an area of the retina;

FIG. 10 is an illustration of a cross-sectional view of a diseased humanretina before treatment with the present invention; and

FIG. 11 is a cross-sectional view similar to FIG. 10, illustrating theportion of the retina after treatment using the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention relates to a system and process for treatingretinal diseases, including vascular retinal diseases such as diabeticretinopathy and diabetic macular edema, by means of predeterminedparameters producing harmless, true subthreshold photocoagulation. Theinventor's finding that retinal laser treatment that does not cause anylaser-induced retinal damage, but can be at least as effective asconventional retinal photocoagulation is contrary to conventionalthinking and practice.

Conventional thinking assumes that the physician must intentionallycreate retinal damage as a prerequisite to therapeutically effectivetreatment. With reference to FIG. 2, FIGS. 2A-2F are graphicrepresentations of the effective surface area of various modes ofretinal laser treatment for retinal vascular disease. The graybackground represents the retina 30 which is unaffected by the lasertreatment. The black areas 32 are areas of the retina which aredestroyed by conventional laser techniques. The lighter gray or whiteareas 34 represent the areas of the retina affected by the laser, butnot destroyed.

FIG. 2A illustrates the therapeutic effect of conventional argon laserretinal photocoagulation. The therapeutic effects attributed tolaser-induced thermal retinal destruction include reduced metabolicdemand, debulking of diseased retina, increased intraocular oxygentension and ultra production of vasoactive cytokines, including vascularendothelial growth factor (VEGF).

With reference to FIG. 2B, increasing the burn intensity of thetraditional laser burn is shown. It will be seen that the burned anddamaged tissue area 32 is larger, which has resulted in a larger “haloeffect” of heated, but undamaged, surrounding tissue 34. Laboratorystudies have shown that increased burn intensity is associated with anenhanced therapeutic effect, but hampered by increased loss offunctional retina inflammation. However, with reference to FIG. 2C, whenthe intensity of the conventional argon laser photocoagulation isreduced, the area of the retina 34 affected by the laser but notdestroyed is also reduced, which may explain the inferior clinicalresults from lower-intensity/lower-density or “mild” argon laser gridphotocoagulation compared to higher-intensity/higher-density treatment,as illustrated in FIG. 2B.

With reference to FIG. 2D, it has been found that low-fluencephotocoagulation with short-pulse continuous wave laserphotocoagulation, also known as selective retinal therapy, producesminimal optical and lateral spread of laser photothermal tissue effects,to the extent that the area of the retina affected by the laser but notdestroyed is minimal to nonexistent. Thus, despite complete oblation ofthe directly treated retina 30, the rim of the therapeutically affectedand surviving tissue is scant or absent. This explains the recentreports finding superiority of conventional argon laser photocoagulationover PASCAL for diabetic retinopathy.

However, the inventor has questioned whether such thermal retinal damageis necessary, and whether it accounts for the benefits of theconventional laser treatments. Instead, the inventor has surmised thatthe therapeutic alterations in the retinal pigment epithelium (RPE)cytokine production elicited by conventional photocoagulation comes fromcells at the margins of traditional laser burns, affected but not killedby the laser exposure, referred to by the reference number 34 in FIG. 2.

FIG. 2E represents the use of a low-intensity and low-densitymicropulsed laser, such as a micropulsed diode laser. This createssubthreshold retinal photocoagulation, shown by the reference number 34,without any visible burn areas 32. All areas of the retinal pigmentepithelium exposed to the laser irradiation are preserved, and availableto contribute therapeutically.

The subthreshold retinal photocoagulation is defined as retinal laserapplications biomicroscopically invisible at the time of treatment.Unfortunately, the term has often been used in the art to describeseveral different clinical scenarios reflecting widely varying degreesof laser-induced thermal retinal damage. The use of the term“subthreshold” falls into three categories reflecting common usage andthe historical and morphological evolution of reduced-intensityphotocoagulation for retinal vascular disease toward truly invisiblephototherapy which the invention embodies.

“Classical subthreshold” for photocoagulation describes the earlyattempts at laser intensity reduction using conventional continuousargon, krypton, and diode lasers. Although the retinal burns werenotably less obvious than the conventional “threshold” (photocoagulationconfined to the outer retina and thus less visible at time of treatment)or even milder “suprathreshold” (full-thickness retinal photocoagulationgenerally easily visible at the time of treatment), the lesions of“classical” subthreshold photocoagulation were uniformly visible bothclinically and by fundus fluorescein angiography (FFA) at the time oftreatment and thereafter.

“Clinical subthreshold” photocoagulation describes the next epiphany ofevolution of laser-induced retinal damage reduction, describing alower-intensity but persistently damaging retinal photocoagulation usingeither a micropulsed laser or short-pulsed continuous wave laser thatbetter confine the damage to the outer retina and retinal pigmentationepithelium. In “clinical” subthreshold photocoagulation, the laserlesions may in fact be ophthalmoscopically invisible at the time oftreatment, however, as laser-induced retinal damage remains the intendedpoint of treatment, laser lesions are produced which generally becomeincreasingly clinically visible with time, and many, if not all, laserlesions can be seen by FFA, fundus autofluorescence photography (FAF),and/or spectral-domain (SD) optical coherence tomography (OCT) at thetime of treatment and thereafter.

“True” subthreshold photocoagulation, as a result of the presentinvention, is invisible and includes laser treatment non-discernable byany other known means such as FFA, FAF, or even SD-OCT. “Truesubthreshold” photocoagulation is therefore defined as a laser treatmentwhich produces absolutely no retinal damage detectable by any means atthe time of treatment or any time thereafter by known means ofdetection. As such, with the absence of lesions and other tissue damageand destruction, FIGS. 2E and 2F represent the result of “true”,invisible subthreshold photocoagulation.

Various parameters have been determined to achieve “true” subthresholdor “low-intensity” effective photocoagulation. These include providingsufficient power to produce effective treatment retinal laser exposure,but not too high to create tissue damage or destruction. Truesubthreshold laser applications can be applied singly or to create ageometric object or pattern of any size and configuration to minimizeheat accumulation, but assure uniform heat distribution as well asmaximizing heat dissipation, and using a low duty cycle. The inventorhas discovered how to achieve therapeutically effective and harmlesstrue subthreshold retinal laser treatment. The inventor has alsodiscovered that placement of true subthreshold laser applicationsconfluently and contiguously to the retinal surface improves andmaximizes the therapeutic benefits of treatment without harm or retinaldamage.

The American Standards Institute (ANSI) has developed standards for safeworkplace laser exposure based on the combination of theoretical andempirical data. The “maximum permissible exposure” (MPE) is the safetylevel, set at approximately 1/10^(th) of the laser exposure levelexpected to produce biological effects. At a laser exposure level of 1times MPE, absolute safety would be expected and retinal exposure tolaser radiation at this level would be expected to have no biologicaffect. Based on ANSI data, a 50% of some risk of suffering a barelyvisible (threshold) retinal burn is generally encountered at 10 timesMPE for conventional continuous wave laser exposure. For a low-dutycycle micropulsed laser exposure of the same power, the risk ofthreshold retinal burn is approximately 100 times MPE. Thus, thetherapeutic range—the interval of doing nothing at all and the 50% ofsome likelihood of producing a threshold retinal burn—for low-duty cyclemicropulsed laser irradiation is 10 times wider than for continuous wavelaser irradiation with the same energy. It has been determined that safeand effective subthreshold photocoagulation using a micropulsed diodelaser is between 18 times and 55 times MPE, with a preferred laserexposure to the retina at 47 times RPE for a near-infrared 810 nm diodelaser. At this level, the inventor has observed that there istherapeutic effectiveness with no discernible retinal damage whatsoever.

It has been found that the intensity or power of a laser beam between100 watts to 590 watts per square centimeter is effective yet safe. Aparticularly preferred intensity or power of the laser light beam isapproximately 350 watts per square centimeter for an 810 nm micropulseddiode laser.

Power limitations in current micropulsed diode lasers require fairlylong exposure duration. The longer the laser exposure, the moreimportant the center-spot heat dissipating ability toward the unexposedtissue at the margins of the laser spot and toward the underlyingchoriocapillaris. Thus, the micropulsed laser light beam of an 810 nmdiode laser should have an exposure envelope duration of 500milliseconds or less, and preferably approximately 300 milliseconds. Ofcourse, if micropulsed diode lasers become more powerful, the exposureduration will be lessened accordingly.

Another parameter of the present invention is the duty cycle (thefrequency of the train of micropulses, or the length of the thermalrelaxation time in between consecutive pulses). It has been found thatthe use of a 10% duty cycle or higher adjusted to deliver micropulsedlaser at similar irradiance at similar MPE levels significantly increasethe risk of lethal cell injury, particularly in darker fundi. However,duty cycles less than 10%, and preferably approximately 5% duty cycle(or less) demonstrated adequate thermal rise and treatment at the levelof the MPE cell to stimulate a biologic response, but remained below thelevel expected to produce lethal cell injury, even in darkly pigmentedfundi. Moreover, if the duty cycle is less than 5%, the exposureenvelope duration in some instances can exceed 500 milliseconds.

In a particularly preferred embodiment, the use of small retinal laserspots is used. This is due to the fact that larger spots can contributeto uneven heat distribution and insufficient heat dissipation within thelarge retinal laser spot, potentially causing tissue damage or eventissue destruction towards the center of the larger laser spot. In thisusage, “small” would generally apply to retinal spots less than 1 mm indiameter. However, the smaller the retinal spot, the more ideal the heatdissipation and uniform energy application becomes. Thus, at the powerintensity and exposure duration described above, small spots, such asalong the size of the wavelength of the laser, or small geometric linesor other objects are preferred so as to maximize even heat distributionand heat dissipation to avoid tissue damage.

Thus, the following key parameters have been found in order to createharmless, “true” subthreshold photocoagulation in accordance with thepresent invention: a) a low (preferably 5% or less) duty cycle; b) asmall spot size to minimize heat accumulation and assure uniform heatdistribution within a given laser spot so as to maximize heatdissipation; c) sufficient power to produce retinal laser exposures ofbetween 18 times-55 times MPE producing an RPE temperature rise of 7°C.-14° C.; and retinal irradiance of between 100-590 W/cm².

Using the foregoing parameters, a harmless, “true” subthresholdphotocoagulation phototherapy treatment can be attained which has beenfound to produce the benefits of conventional photocoagulationphototherapy, but avoid the drawbacks and complications of conventionalphototherapy. In fact, “true” subthreshold photocoagulation phototherapyin accordance with the present invention enables the physician to applya “low-intensity/high-density” phototherapy treatment, such asillustrated in FIG. 2F, and treat the entire retina, including sensitiveareas such as the macula and even the fovea without creating visual lossor other damage. As indicated above, using conventional phototherapies,the entire retina, and particularly the fovea, cannot be treated as itwill create vision loss due to the tissue damage in sensitive areas.

Conventional retina-damaging laser treatment is limited in treatmentdensity, requiring subtotal treatment of the retina, including subtotaltreatment of the particular areas of retinal abnormality. However,recent studies demonstrate that eyes in diabetics may have diffuseretinal abnormalities without otherwise clinically visible diabeticretinopathy, and eyes with localized areas of clinically identifiableabnormality, such as diabetic macular edema or central serouschorioretinopathy, often have total retinal dysfunction detectable onlyby retinal function testing. The ability of the invention to harmlesslytreat the entire retina thus allows, for the first time, bothpreventative and therapeutic treatment of eyes with retinal diseasecompletely rather than locally or subtotally; and early treatment priorto the manifestation of clinical retinal disease and visual loss.

As discussed above, it is conventional thinking that tissue damage andlesions must be created in order to have a therapeutic effect. However,the invention has found that this simply is not the case. In the absenceof laser-induced retinal damage, there is no loss of functional retinaltissue and no inflammatory response to treatment. Adverse treatmenteffects are thus completely eliminated and functional retina preservedrather than sacrificed. This may yield superior visual acuity resultscompared to conventional photocoagulation treatment.

The present invention spares the neurosensory retina and is selectivelyabsorbed by the RPE. Current theories of the pathogenesis of retinalvascular disease especially implicate cytokines, potent extra cellularvasoactive factors produced by the RPE, as important mediators ofretinal vascular disease. The present invention both selectively targetsand avoids lethal buildup within RPE. Thus, with the present inventionthe capacity for the treated RPE to participate in a therapeuticresponse is preserved and even enhanced rather than eliminated as aresult their destruction of the RPE in conventional photocoagulationtherapies.

It has been noted that the clinical effects of cytokines may follow a“U-shaped curve” where small physiologic changes in cytokine production,denoted by the left side of curve, may have large clinical effectscomparable to high-dose (pharmacologic) therapy (denoted by the rightside of the curve). Using sublethal laser exposures in accordance withthe present invention may be working on the left side of the curve wherethe treatment response may approximate more of an “on/off” phenomenonrather than a dose-response. This might explain the clinicaleffectiveness of the present invention observed at low reportedirradiances. This is also consistent with clinical experience andin-vitro studies of laser-tissue interaction, wherein increasingirradiance may simply increase the risk of thermal retinal damagewithout improving the therapeutic effect.

With reference again to FIG. 2, the invisible, true subthresholdphotocoagulation phototherapy maximizes the therapeutic recruitment ofthe RPE through the concept of “maximize the affected surface area”, inthat all areas of RPE exposed to the laser irradiation are preserved,and available to contribute therapeutically. As discussed above withrespect to FIG. 2, it is believed that conventional therapy creates atherapeutic ring around the burned or damaged tissue areas, whereas thepresent invention creates a therapeutic area without any burned orotherwise destroyed tissue.

In another departure from conventional retinal photocoagulation, a lowred to infrared laser light beam, such as from an 810 nm micropulseddiode laser, is used instead of an argon laser. It has been found thatthe 810 nm diode laser is minimally absorbed and negligibly scattered byintraretinal blood, cataract, vitreous hemorrhage and even severelyedematous neurosensory retina. Differences in fundus coloration resultprimarily from differences in choroid pigmentation, and less ofvariation of the target RPE. Treatment in accordance with the presentinvention is thus simplified, requiring no adjustment in laserparameters for variations in macular thickening, intraretinalhemorrhage, mediaopacity or fundus pigmentation, reducing the risk oferror.

However, it is contemplated that the present invention could be utilizedwith micropulsed emissions of shorter wavelengths, such as the recentlyavailable 577 nm yellow and 532 nm green lasers. The higher energies anddifferent tissue absorption characteristic of shorter wavelength lasersmay increase retinal burn risk, effectively narrowing the therapeuticwindow. In addition, the shorter wavelengths are more scattered byopaque ocular media, retinal hemorrhage and macular edema, potentiallylimiting usefulness and increasing the risk of retinal damage in certainclinical settings. Thus, a low red to infrared laser light beam is stillpreferred.

In fact, low power red and near-infrared laser exposure is known toaffect many cell types, particularly altering the behavior of cells andpathological environments, such as diabetes, through a variety ofintracellular photoreceptors. Cell function, in cytokine expression, isnormalized and inflammation reduced. By normalizing function of theviable RPE cells, the invention may induce changes in the expression ofmultiple factors physiologically as opposed to drug therapy thattypically narrowly targets only a few post-cellular factorspharmacologically. The laser-induced physiologic alteration of RPEcytokine expression may account for the slower onset but long lastingbenefits using the present invention. Furthermore, use of aphysiologically invisible infrared or near-infrared laser wavelength isperceived as comfortable by the patient, and does not cause reactivepupillary constriction, allowing visualization of the ocular fundus andtreatment of the retina to be performed without pharmacologic dilationof the patient pupil. This also eliminates the temporary of visualdisability typically lasting many hours following pharmacologicpupillary dilation currently required for treatment with conventionallaser photocoagulation. Currently, patient eye movement is a concern notonly for creating the pattern of laser spots to treat the intended area,but also could result in exposure of conventional therapy to sensitiveareas of the eye, such as the fovea, resulting in loss of vision orother complications.

With reference now to FIG. 3, a schematic diagram is shown of a systemfor realizing the process of the present invention. The system,generally referred to by the reference number 40, includes a laserconsole 42, such as for example the 810 nm near infrared micropulseddiode laser in the preferred embodiment. The laser generates a laserlight beam which is passed through an optical lens or mask, or aplurality of optical lenses and/or masks 44 as needed. The laserprojector optics 44 pass the shaped light beam to a coaxial wide-fieldnon-contact digital optical viewing system/camera 46 for projecting thelaser beam light onto the eye 48 of the patient. It will be understoodthat the box labeled 46 can represent both the laser beam projector aswell as a viewing system/camera, which might in reality comprise twodifferent components in use. The viewing system/camera 46 providesfeedback to a display monitor 50, which may also include the necessarycomputerized hardware, data input and controls, etc. for manipulatingthe laser 42, the optics 44, and/or the projection/viewing components46.

As discussed above, current treatment requires the application of alarge number of individual laser beam spots applied to the target tissueto be treated. These can number in the hundreds or even thousands forthe desired treatment area. This is very time intensive and laborious.

With reference now to FIG. 4, in one embodiment, the laser light beam 52is passed through a collimater lens 54 and then through a mask 56. In aparticularly preferred embodiment, the mask 56 comprises a diffractiongrating. The mask/diffraction grating 56 produces a geometric object, ormore typically a geometric pattern of simultaneously produced multiplelaser spots or other geometric objects. This is represented by themultiple laser light beams labeled with reference number 58. Usingdiffraction gratings or other diffraction optics allows use of a verylow power lasers to drive the system of the present invention. Thisallows the creation of a very large number of laser spots simultaneouslyover a very wide treatment field, such as consisting of the entireretina. In fact, a very high number of laser spots, perhaps numbering inthe thousands or even ten thousand or more could cover the entire ocularfundus and entire retina, including the macula and fovea, retinal bloodvessels and optic nerve. The intent of the process in the presentinvention is to better ensure complete and total coverage and treatment,sparing none of the retina by the laser so as to improve vision.

Using a diffraction apertures of a size on par with the wavelength ofthe laser employed, it is possible to take advantage of quantummechanical effects which significantly increases the output irradiance,and permits simultaneous application of very large number ofsimultaneously applied laser spots for a very large target area drivenby very low power input laser. The individual spots produced by suchdiffraction gratings can be smaller in the order of magnitudes, withsuch small spot sizes having not been employed in the treatment of theretina previously. Of course, such small sizes minimize the risk ofsingle-spot heat damage due to their small size and due to the spacingof the small spots allow heat diffusion readily. However, the presentinvention also contemplates the use of conventionally sized (50-500 μm)generated individual spots as well as other geometric objects andpatterns.

The laser light passing through the mask 56 diffracts, producing aperiodic pattern a distance away from the mask 56, shown by the laserbeams labeled 58 in FIG. 4. The single laser beam 52 has thus beenformed into hundreds or thousands or even tens of thousands ofindividual laser beams 58 so as to create the desired pattern of spotsor other geometric objects. These laser beams 58 may be passed throughadditional lenses, collimaters, etc. 60 and 62 in order to convey thelaser beams and form the desired pattern on the patient's retina. Suchadditional lenses, collimaters, etc. 60 and 62 can further transform andredirect the laser beams 58 as needed.

Arbitrary patterns can be constructed by controlling the shape, spacingand pattern of the optical mask 56. The pattern and exposure spots canbe created and modified arbitrarily as desired according to applicationrequirements by experts in the field of optical engineering.Photolithographic techniques, especially those developed in the field ofsemiconductor manufacturing, can be used to create the simultaneousgeometric pattern of spots or other objects.

Typically, the system of the present invention incorporates a guidancesystem to ensure complete and total retinal treatment with retinalphotostimulation. As the treatment method of the present invention isharmless, the entire retina, including the fovea and even optical nerve,can be treated. Moreover, protection against accidental visual loss byaccidental patient movement is not a concern. Instead, patient movementwould mainly affect the guidance in tracking of the application of thelaser light to ensure adequate coverage. Fixation/tracking/registrationsystems consisting of a fixation target, tracking mechanism, and linkedto system operation are common in many ophthalmic diagnostic systems andcan be incorporated into the present invention.

With reference now to FIGS. 5 and 6, in a particularly preferredembodiment, the geometric pattern of simultaneous laser spots issequentially offset so as to achieve confluent and complete treatment ofthe retinal surface. Although a segment of the retina can be treated inaccordance with the present invention, more typically the entire retinawill be treated with one treatment. This is done in a time-saving mannerby placing thousands of spots over the entire ocular fundus at once.This pattern of spots is scanned, shifted, or redirected as an entirearray simultaneously, so as to cover the entire retina.

This can be done in a controlled manner using an optical scanningmechanism 64 such as that illustrated in FIGS. 5 and 6. FIGS. 5 and 6illustrate an optical scanning mechanism 64 in the form of a MEMSmirror, having a base 66 with electronically actuated controllers 68 and70 which serve to tilt and pan the mirror 72 as electricity is appliedand removed thereto. Applying electricity to the controller 68 and 70causes the mirror 72 to move, and thus the simultaneous pattern of laserspots or other geometric objects reflected thereon to move accordinglyon the retina of the patient. This can be done, for example, in anautomated fashion using electronic software program to adjust theoptical scanning mechanism 64 until complete coverage of the retina, orat least the portion of the retina desired to be treated, is exposed tothe phototherapy.

Since the parameters of the present invention dictate that the appliedlaser light is not destructive or damaging, the geometric pattern oflaser spots, for example, can be overlapped without creating any damage.However, in a particularly preferred embodiment, as illustrated in FIG.7, the pattern of spots are offset at each exposure so as to createspace between the immediately previous exposure to allow heatdissipation and prevent the possibility of heat damage or tissuedestruction. Thus, as illustrated in FIG. 7, the pattern, illustratedfor exemplary purposes as a grid of sixteen spots, is offset eachexposure such that the laser spots occupy a different space thanprevious exposures. It will be understood that this occurs until theentire retina, the preferred methodology, has received phototherapy, oruntil the desired effect is attained. This can be done, for example, byapplying electrostatic torque to a micromachined mirror, as illustratedin FIGS. 5 and 6. By combining the use of small retina laser spotsseparated by exposure free areas, prevents heat accumulation, and gridswith a large number of spots per side, it is possible to atraumaticallyand invisibly treat large target areas with short exposure durations farmore rapidly than is possible with current technologies.

By rapidly and sequentially repeating redirection or offsetting of theentire simultaneously applied grid array of spots or geometric objects,complete coverage of the target, such as a human retina, can be achievedrapidly without thermal tissue injury. This offsetting can be determinedalgorithmically to ensure the fastest treatment time and least risk ofdamage due to thermal tissue, depending on laser parameters and desiredapplication. The following has been modeled using the FraunhofferApproximation. With a mask having a nine by nine square lattice, with anaperture radius 9 μm, an aperture spacing of 600 μm, using a 890 nmwavelength laser, with a mask-lens separation of 75 mm, and secondarymask size of 2.5 mm by 2.5 mm, the following parameters will yield agrid having nineteen spots per side separated by 133 μm with a spot sizeradius of 6 μm. The number of exposures “m” required to treat (coverconfluently with small spot applications) given desired area side-length“A”, given output pattern spots per square side “n”, separation betweenspots “R”, spot radius “r” and desired square side length to treat area“A”, can be given by the following formula:

$m = {\frac{A}{nR}\mspace{11mu}{floor}\mspace{14mu}\left( \frac{R}{2\; r} \right)^{2}}$

With the foregoing setup, one can calculate the number of operations mneeded to treat different field areas of exposure. For example, a 3 mm×3mm area, which is useful for treatments, would require 98 offsettingoperations, requiring a treatment time of approximately thirty seconds.Another example would be a 3 cm×3 cm area, representing the entire humanretinal surface. For such a large treatment area, a much largersecondary mask size of 25 mm by 25 mm could be used, yielding atreatment grid of 190 spots per side separated by 133 μm with a spotsize radius of 6 μm. Since the secondary mask size was increased by thesame factor as the desired treatment area, the number of offsettingoperations of approximately 98, and thus treatment time of approximatelythirty seconds, is constant. These treatment times represent at leastten to thirty times reduction in treatment times compared to currentmethods of sequential individual laser spot applications. Field sizes of3 mm would, for example, allow treatment of the entire human macula in asingle exposure, useful for treatment of common blinding conditions suchas diabetic macular edema and age-related macular degeneration.Performing the entire 98 sequential offsettings would ensure entirecoverage of the macula.

Of course, the number and size of retinal spots produced in asimultaneous pattern array can be easily and highly varied such that thenumber of sequential offsetting operations required to completetreatment can be easily adjusted depending on the therapeuticrequirements of the given application.

Furthermore, by virtue of the small apertures employed in thediffraction grading or mask, quantum effects such as constructiveinterference may be observed which magnify the input irradiance. Thiswould allow use of relatively low power in widely available source inputlasers, and allow therapeutically effective low-duty cycle diode lasermicropulsed retinal irradiation, such as 350 watts per centimetersquared known to be safe and effective, over a treatment field of novelsize, such as the 1.2 cm area to accomplish whole-retinal treatment.

With reference now to FIG. 8, instead of a geometric pattern of smalllaser spots, the present invention contemplates use of other geometricobjects or patterns. For example, a single line 74 of laser light,formed by the continuously or by means of a series of closely spacedspots, can be created. An offsetting optical scanning mechanism can beused to sequentially scan the line over an area, illustrated by thedownward arrow in FIG. 8.

With reference now to FIG. 9, the same geometric object of a line 74 canbe rotated, as illustrated by the arrows, so as to create a circularfield of phototherapy. The potential negative of this approach, however,is that the central area will be repeatedly exposed, and could reachunacceptable temperatures. This could be overcome, however, byincreasing the time between exposures, or creating a gap in the linesuch that the central area is not exposed.

With reference again to FIG. 3, due to the unique characteristics of thepresent invention, allowing a single set of optimized laser parameters,which are not significantly influenced by media opacity, retinalthickening, or fundus pigmentation, a simplified user interface ispermitted. While the operating controls could be presented and functionin many different ways, the system permits a very simplified userinterface that might employ only two control functions. That is, an“activate” button, wherein a single depression of this button while in“standby” would actuate and initiate treatment. A depression of thisbutton during treatment would allow for premature halting of thetreatment, and a return to “standby” mode. The activity of the machinecould be identified and displayed, such as by an LED adjacent to orwithin the button. A second controlled function could be a “field size”knob. A single depression of this button could program the unit toproduce, for example, a 3 mm focal or a “macular” field spot. A seconddepression of this knob could program the unit to produce a 6 mm or“posterior pole” spot. A third depression of this knob could program theunit to produce a “pan retinal” or approximately 160°-220° panoramicretinal spot or coverage area. Manual turning of this knob could producevarious spot field sizes therebetween. Within each field size, thedensity and intensity of treatment would be identical. Variation of thefield size would be produced by optical or mechanical masking orapertures.

The laser could be projected via a wide field non-contact lens to theocular fundus. Customized direction of the laser fields or particulartarget or area of the ocular fundus other than the central area could beaccomplished by an operator joy stick or eccentric patient gaze. Thelaser delivery optics could be coupled coaxially to a wide fieldnon-contact digital ocular fundus viewing system. The image of theocular fundus produced could be displayed on a video monitor visible tothe laser operator. Maintenance of a clear and focused image of theocular fundus could be facilitated by a joy stick on the camera assemblymanually directed by the operator. Alternatively, addition of a targetregistration and tracking system to the camera software would result ina completely automated treatment system.

A fixation image could be coaxially displayed to the patient tofacilitate ocular alignment. This image would change in shape and size,color, intensity, blink or oscillation rate or other regular orcontinuous modification during treatment to avoid photoreceptorexhaustion, patient fatigue and facilitate good fixation.

Fixation software could monitor the displayed image of the ocularfundus. Prior to initiating treatment of a fundus landmark, such as theoptic nerve, or any part or feature of either eye of the patient(assuming orthophoria), could be marked by the operator on the displayscreen. Treatment could be initiated and the software would monitor thefundus image or any other image-registered to any part of either eye ofthe patient (assuming orthophoria) to ensure adequate fixation. A breakin fixation would automatically interrupt treatment. Treatment wouldautomatically resume toward completion as soon as fixation wasestablished. At the conclusion of treatment, determined by completion ofconfluent delivery of the desired laser energy to the target, the unitwould automatically terminate exposure and default to the “on” or“standby” mode. Due to unique properties of this treatment, fixationinterruption would not cause harm or risk patient injury, but onlyprolong the treatment session.

With reference now to FIGS. 10 and 11, spectral-domain OCT imaging isshown in FIG. 10 of the macular and foveal area of the retina beforetreatment with the present invention. FIG. 11 is of the opticalcoherence tomography (OCT) image of the same macula and fovea aftertreatment using the present invention, using a 131 micrometer retinalspot, 5% duty cycle, 0.3 second pulse duration, 0.9 watt power placedthroughout the area of macular thickening, including the fovea. It willbe noted that the enlarged dark area to the left of the fovea depression(representing the pathologic retinal thickening of diabetic macularedema) is absent, as well as the fact that there is an absence of anylaser-induced retinal damage. Such treatment simply would not beattainable with conventional techniques.

Although the present invention is particularly suited for treatment ofvascular retinal diseases, such as diabetic retinopathy and macularedema, it is contemplated that it could be used for other diseases aswell. The system and process of the present invention could target thetrabecular mesh work as treatment for glaucoma, accomplished by anothercustomized treatment field template. It is contemplated by the presentinvention that the system and concepts of the present invention beapplied to phototherapy treatment of other tissues, such as, but notlimited to, the gastrointestinal or respiratory mucosa, deliveredendoscopically, for other purposes.

Although several embodiments have been described in detail for purposesof illustration, various modifications may be made without departingfrom the scope and spirit of the invention. Accordingly, the inventionis not to be limited, except as by the appended claims.

What is claimed is:
 1. A system for treating a retinal disease ordisorder, comprising: a laser producing a micropulsed light beam havingparameters, including an average power intensity of between 100-590watts per square centimeter of exposed retina tissue, a micropulse trainduration of between 100 to 500 milliseconds, and a duty cycle of lessthan 10%, that provide retinal therapy while not destroying retinaland/or foveal tissue; optics, comprising an optical mask, for opticallyshaping the light beam from the laser into at least sixteen spaced apartlaser light beams forming a simultaneously applied geometric pattern ofspots on the retina, each having a size between 100 and 500 micrometers;and an optical scanning mechanism for controllably directing the lightbeams onto at least a portion of a retina and a fovea of an eve withoutdamaging retinal or foveal tissue.
 2. The system of claim 1, wherein theduty cycle of the laser is approximately 5%.
 3. The system of claim 1,wherein the intensity of the laser is approximately 350 watts per squarecentimeter.
 4. The system of claim 1, wherein the optical scanningmechanism controllably moves the light beams until substantially all ofthe retina and the fovea has been exposed to the light beams.
 5. Thesystem of claim 1, wherein the optical scanning mechanism applies thelight beam object or pattern to the retina and/or the fovea at 18 to 55times the American National Standards Institute Maximum PermissibleExposure level.
 6. The system of claim 1, wherein the optics diffractthe light beam into a plurality of light beams.
 7. The system of claim1, wherein the laser produces a light beam having a wavelength of atleast 532 nm.
 8. The system of claim 1, wherein the laser produces alight beam having a wavelength between 750 nm-1300 nm.
 9. The system ofclaim 8, wherein the laser light beam has a wavelength of approximately810 nm.
 10. A system for treating a retinal disease or disorder,comprising: a laser producing a micropulsed light beam havingparameters, including a wavelength greater than 532 nm, an average powerintensity of between 100-590 watts per square centimeter of exposedretina tissue, a micropulse train duration of between 100 to 500milliseconds, and a duty cycle of less than 10%, so as to createharmless subthreshold photocoagulation when the laser light beam isapplied to retinal and/or fovea tissue; optics, comprising an opticalmask, for optically diffracting and shaping the light beam from thelaser into a simultaneous geometric object or pattern of at leastsixteen spaced apart laser light spots; and an optical scanningmechanism for controllably directing the light beam object or patternonto at least a portion of a retina and a fovea without damaging retinalor foveal tissue.
 11. The system of claim 10, wherein the duty cycle ofthe laser is approximately 5%.
 12. The system of claim 10, wherein theintensity of the laser is between 100-590 watts per square centimeter.13. The system of claim 10, wherein the optical scanning mechanismcontrollably moves the spaced apart laser light spots untilsubstantially all of the retina and the fovea has been exposed to thelight beam.
 14. The system of claim 10, wherein the optical scanningmechanism applies the light beam object or pattern to the retina and/orthe fovea at 18 to 55 times the American National Standards InstituteMaximum Permissible Exposure level.
 15. The system of claim 10, whereinthe laser produces a light beam having a wavelength between 750 nm-1300nm.
 16. The system of claim 15, wherein the laser light beam has awavelength of approximately 810 nm.